| Literature DB >> 33450196 |
Peter Kalev1, Marc L Hyer2, Stefan Gross3, Zenon Konteatis4, Chi-Chao Chen5, Mark Fletcher5, Max Lein6, Elia Aguado-Fraile7, Victoria Frank1, Amelia Barnett1, Everton Mandley2, Joshua Goldford8, Yue Chen6, Katie Sellers8, Sebastian Hayes8, Kate Lizotte8, Phong Quang1, Yesim Tuncay1, Michelle Clasquin8, Rachel Peters9, Jaclyn Weier1, Eric Simone10, Joshua Murtie11, Wei Liu5, Raj Nagaraja6, Lenny Dang3, Zhihua Sui4, Scott A Biller4, Jeremy Travins4, Kevin M Marks1, Katya Marjon12.
Abstract
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.Entities:
Keywords: DNA damage; Fanconi anemia complex; MAT2A; PRMT5; R loops; detained introns; splicing; synergy; taxanes
Year: 2021 PMID： 33450196 DOI： 10.1016/j.ccell.2020.12.010
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743